Control of airway inflammation and Th2 differentiation by microRNA 21

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DESCRIPTION (provided by applicant): The incidence of Th2 cell-mediated atopic and allergic diseases are increasing dramatically worldwide, with almost 50% of the urban population presenting with atopic diseases including asthma, rhino- conjunctivitis, sinusitis, food allergy, and atopic dermatitis. Thus, new diagnostic markers and treatments for allergic diseases remain a high priority. Micro-RNAs (miRs) are important regulators of gene expression, and in particular, miRs critically control immune system function. MiRs are deregulated in many pathologic conditions, and miRs have been studied extensively in cancer and the inflammation associated with cancer. The role of miRs in other types of inflammation is a relatively new area of investigation, and little is known about miRs in allergic disease and allergic inflammation. MiR21 was found to be highly up-regulated in lungs with Th2-type allergic inflammation, and we recently have found that more severe allergic inflammation in the lung correlates with strongly increased miR21 expression. We have further established that increased miR21 expression in T cells can promote Th2 differentiation. Thus, we hypothesize that during inflammatory conditions, high miR21 expression promotes further inflammation and amplified Th2 differentiation. This hypothesis predicts that blocking miR21 can alleviate Th2-type inflammation, and in this proposal we will test miR21 inhibition as a potential therapy for allergic disease. We will further define the role of miR21 in Th2 differentiation and inflammation, by elucidating the mechanism by which miR21 promotes Th2 differentiation. We will also analyze what specific cell types up-regulate miR21 during inflammation. MiR21 transcription is induced by activated STAT3, and we have determined that miR21 transcription is repressed by BCL6. We will explore the relationship of BCL6 repression of miR21 to activation by STAT3, and if there is an antagonistic regulation of miR21 by STAT3 and BCL6 that controls Th2 differentiation. These studies have the potential to lead to new treatments for allergic disease, as well as provide novel insights into the pathogenic mechanisms of allergy and atopy.